Activation of JUN in fibroblasts promotes pro-fibrotic programme and modulates protective immunity

The transcription factor JUN is highly expressed in pulmonary fibrosis. Its induction in mice drives lung fibrosis, which is abrogated by administration of anti-CD47. Here, we use high-dimensional mass cytometry to profile protein expression and secretome of cells from patients with pulmonary fibrosis. We show that JUN is activated in fibrotic fibroblasts that expressed increased CD47 and PD-L1. Using ATAC-seq and ChIP-seq, we found that activation of JUN rendered promoters and enhancers of CD47 and PD-L1 accessible. We further detect increased IL-6 that amplified JUN-mediated CD47 enhancer activity and protein expression. Using an in vivo mouse model of fibrosis, we found two distinct mechanisms by which blocking IL-6, CD47 and PD-L1 reversed fibrosis, by increasing phagocytosis of profibrotic fibroblasts and by eliminating suppressive effects on adaptive immunity. Our results identify specific immune mechanisms that promote fibrosis and suggest a therapeutic approach that could be used alongside conventional anti-fibrotics for pulmonary fibrosis.


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Genome browser session  Supplementary table 1 We received primary lung tissues exclusively from patients with end-stage pulmonary fibrosis undergoing transplantation. Therefore, our cohort of patients represents severely fibrotic lung disease. It has been challenging to receive normal control lung tissues. While we have received lung tissues from normal lung resections from tumor resections from Stanford tissue bank as well as lungs from rapid autopsies, it appeared that the only normal lung tissues harvested during surgery by the tissue bank were of sufficient viability to include in our CyTOF studies; while other cell-type fractions appeared representative we noted a bias towards less endothelial cells in the normal biopsies due to the relatively small amounts of lung tissue we received from the tissue bank.
Human samples were obtained under Stanford University's IRB approval.